Project Summary Rodent-borne viral outbreaks are increasing in both frequency and impact. As weather patterns evolve, rodent populations are affected and may multiply in areas where increased contact with humans results in infection. Hantaviruses, including Andes (ANDV) and Sin Nombre (SNV), are transmitted through the excreta of infected rodents and, when aerosolized, infect humans. In the Americas, hantavirus infection leads to hantavirus cardiopulmonary syndrome (HCPS), a devastating condition that features rapid onset of pulmonary edema, respiratory failure and cardiogenic shock. Treatment is supportive, not pathogen-targeted, and accordingly, approximately 40% of patients do not survive. Because hantaviruses establish lifelong, asymptomatic infections in their rodent reservoirs, they are highly prevalent in nature and represent a constant threat to humans. For example, SNV is carried by the most abundant mammal in North America, the deer mouse, which has a near ubiquitous distribution throughout the US and Canada. In the case of the South American ANDV, in addition to rodent-to-human transmission, human-to-human transmission occurs, putting not only the patient, but also family members and health care workers at risk. Despite this large potential for infection and the high case fatality rate, there are no FDA-approved treatment options or vaccines available. Hantaviruses are thus classified as NIAID Priority Pathogens and considered potential bioterrorism threats. Our long term goal is to develop an effective therapeutic against HCPS-causing hantaviruses. This proposal seeks to develop human neutralizing antibodies for therapeutic and/or prophylactic treatment of HCPS caused by ANDV. We have assembled a multidisciplinary team of molecular virologists, clinicians, B cell immunologists, and industry partners with experience developing antibody-based therapeutics. The successful development of a potent neutralizing antibody against ANDV has the potential to be a first-line antiviral for the treatment or prevention of HCPS.